Figure 50-13 Nitric oxide synthase (NOS) dysfunction induced by glyceryl trinitrate (GTN) therapy. Physiologically, NOS catalyzes a two-step oxidation of L-arginine to L-citrulline and NO. Generation of free ^• O₂ ^- is minimal. The equilibrium between this form of NOS and the uncoupled state (i.e., in which L-arginine is not oxidized and ^• O₂ ^- is generated) appears to depend on the supply of L-arginine and the oxidative status of tetrahydrobiopterin (BH₄ ). During nitrate tolerance, this equilibrium might be shifted toward the uncoupled form of the enzyme. In turn, ^• O₂ ^- and peroxynitrite can oxidize BH₄ , thereby resulting in further uncoupling. Folic acid (possibly though a BH₄ -mediated mechanism) and L-arginine supplementation can reverse this process. BH₂ , dihydrobiopterin; NOS III, endothelial nitric oxide. (Redrawn from Gori T, Parker JD: The puzzle of nitrate tolerance. Pieces smaller than we thought? Circulation 106:2404–2408, 2002.)